Method of forming conductive lines

ABSTRACT

Pharmaceutical solution aerosol formulations comprising beclomethasone 17,21 dipropionate, ethanol, and a propellant selected from the group consisting of 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, and a mixture thereof.

This is a continuation of application Ser. No. 09/110,800 filed Jul. 6,1998, now abandoned, which is a continuation of application Ser. No.08/455,872, filed May 31, 1995, now U.S. Pat. No. 5,776,432, which is acontinuation of application Ser. No. 07/769,547, filed Oct. 1, 1991, nowabandoned, which is a continuation-in-part of application Ser. No.07/599,694, filed Oct. 18, 1990, now abandoned.

TECHNICAL FIELD OF THE INVENTION

This invention pertains to solution aerosol formulations suitable foruse in administering drugs. In another aspect this invention pertains toformulations comprising beclomethasone 17,21 dipropionate.

BACKGROUND OF THE INVENTION

Pharmaceutical suspension aerosol formulations currently use a mixtureof liquid chlorofluorocarbons as the propellant. Fluorotrichloromethane,dichlorodifluoromethane and dichlorotetrafluoroethane are the mostcommonly used propellants in aerosol formulations for administration byinhalation.

Chlorofluorocarbons have been implicated in the destruction of the ozonelayer and their production is being phased out. Hydrofluorocarbon 134a(HFC-134a, 1,1,1,2-tetrafluoroethane) and hydrofluorocarbon 227(HFC-227, 1,1,1,2,3,3,3-heptafluoropropane) are viewed as being lessdestructive to ozone than many chlorofluorocarbon propellants;furthermore, they have low toxicity and vapor pressure suitable for usein aerosols.

Beclomethasone 17,21 dipropionate is commercially available as anaerosol product comprising a suspension of a chlorofluorohydrocarbonsolvate of beclomethasone 17,21 dipropionate in chlorofluorohydrocarbonpropellants. Preparation of the solvate requires several processingsteps and is required in order to obtain a stable aerosol formulation,i.e., one in which the micronized particles of active ingredient remainin the desired respirable particle size range. A solution formulation ofbeclomethasone 17,21 dipropionate could simplify formulation manufactureand increase the respirable fraction (i.e., the percentage of activeingredient able to reach the airways of the lung where thepharmaceutical effect is exerted).

U.S. Pat. No. 2,868,691 discloses a self-propelling pharmaceuticalaerosol formulation comprising i) a medicament; ii) a propellantrepresented generally by the formula C_(m)H_(n)Cl_(y)F_(z), wherein m isan integer less than 3, n is an integer or zero, y is an integer orzero, and z is an integer, such that n+y+z=2m+2; and iii) a cosolventwhich assists in the dissolution of the medicament in the propellant.Ethanol is an example of a cosolvent disclosed in this patent. The aboveformula representing the propellant component generically embracesHFC-134a. This patent does not, however, disclose beclomethasone 17,21dipropionate or suggest how stable solution aerosol formulations (i.e.,formulations that are chemically stable and exhibit desirable respirablefraction) containing any propellant and beclomethasone 17,21dipropionate can be prepared.

SUMMARY OF THE INVENTION

The present invention provides an aerosol formulation comprising atherapeutically effective amount of beclomethasone 17,21 dipropionate, apropellant comprising a hydrofluorocarbon selected from the groupconsisting of 1,1,1,2-tetrafluoroethane,1,1,1,2,3,3,3-heptafluoropropane, and a mixture thereof, and ethanol inan amount effective to solubilize the beclomethasone 17,21 dipropionatein the propellant, the formulation being further characterized in thatsubstantially all of the beclomethasone 17,21 dipropionate is dissolvedin the formulation, and the formulation is substantially free of anysurfactant.

Certain of the preferred formulations of the invention exhibit verydesirable chemical stability and provide respirable fractionssignificantly greater than commercially available beclomethasone 17,21dipropionate products. Moreover, the formulations of the invention areconvenient to manufacture since no solvate of the active ingredient needbe prepared.

The pharmaceutical solution aerosol formulations of the invention aresuitable for pulmonary, buccal, or nasal administration.

DETAILED DESCRIPTION OF THE INVENTION

All weight percentages recited herein are based on the total weight ofthe formulation unless otherwise indicated.

The medicament beclomethasone 17,21 dipropionate is generally present ina formulation of the invention in a therapeutically effective amount,i.e., an amount such that one or more metered volumes of the formulationcontains an amount of drug effective to exert the intended therapeuticaction. Preferably the medicament will constitute about 0.02 to about0.6 percent by weight, more preferably about 0.05 to about 0.5 percentby weight of the total weight of the formulation.

Ethanol is generally present in an amount effective to solubilize thebeclomethasone 17,21 dipropionate in the propellant. Preferably, ethanolconstitutes about 1 to about 20 percent by weight of the total weight ofthe aerosol formulation. More preferably, ethanol constitutes about 2 toabout 12 percent by weight and even more preferably about 2 to about 10percent by weight of the aerosol formulation. Most preferably, ethanolwill be present in an amount sufficient to dissolve substantially all ofthe medicament present in the formulation and to maintain the medicamentdissolved over the time period and conditions experienced by commercialaerosol products, but not substantially in excess of said amount.Particularly desirable formulations of the invention, while notcontaining amounts of ethanol substantially in excess of that required(during manufacture of the formulation) to dissolve the amount of activeingredient employed, may be subjected to a temperature of −20° C.without precipitation of the active ingredient.

The hydrofluorocarbon propellant can be HFC-134a, HFC-227, or a mixturethereof. The propellant preferably constitutes from about 80 to about 99percent by weight, preferably from about 88 to about 98 percent byweight, and more preferably about 90 to about 98 percent by weight ofthe total weight of the aerosol formulation. The hydrofluorocarbonpropellant is preferably the only propellant present in the formulationsof the invention. However, one or more other propellants (e.g.,1-chloro-1,1-difluoroethane) can also be present.

The formulations of the invention are substantially free of anysurfactant. By “substantially free” as used in the instant specificationand claims is meant that the formulations contain no more than 0.0005percent by weight of a surfactant based on the total weight of theformulation. Preferred formulations contain no surfactant. Presence of asignificant amount of a surfactant is believed to be undesirable in thecase of solution formulations of beclomethasone 17,21 dipropionatebecause surfactants such as oleic acid and lecithin seem to promotechemical degradation of the active ingredient when the latter isdissolved in the mixture of HFC-134a and ethanol.

Preferred formulations according to the invention consist essentially ofbeclomethasone 17,21 dipropionate in an amount of about 0.05 to about0.35 percent by weight based on the weight of the total formulation,ethanol in an amount of about 2 to about 8 percent by weight based onthe total weight of the formulation, and 1,1,1,2-tetrafluoroethane.

The solution formulations of the invention can be prepared by dissolvingthe desired amount of beclomethasone 17,21 dipropionate in the desiredamount of anhydrous ethanol accompanied by stirring or sonication. Theaerosol vial may then be filled using conventional cold-fill orpressure-fill methods.

The following examples are provided to illustrate the invention butshould not be construed as limiting the invention.

EXAMPLES 1-7

Formulations containing the following ingredients (TABLE I) in theindicated amounts were prepared with the percentages being expressed inparts by weight based upon the total weight of the particularformulation. The active ingredient employed in preparing theformulations of Examples 2, 3, and 5-7 was beclomethasone dipropionate,USP while that employed in preparing the formulations of Examples 1 and4 was a conventional trichloromonofluoromethane solvate ofbeclomethasone dipropionate. The formulations of Examples 1, 4, 5 and 6were prepared by i) dissolving the active ingredient in the ethanol; ii)metering the solution obtained above into an aluminum vial and crimpinga continuous valve onto the vial; iii) pressure-filling the vial with1,1,1,2-tetrafluoroethane; iv) chilling the vial to −60° C.; and v)replacing the continuous valve with a 50 microliter valve which isavailable under the trade designation “W303-98” from 3M. Theformulations of Examples 2, 3 and 7 were prepared by i) dissolving theactive ingredient in the ethanol; ii) metering the solution obtainedabove into an aluminum vial and crimping a 50 microliter pressure-fillvalve which is available under the trade designation Spraymiser™ M3652from 3M onto the vial; and iii) pressure-filling the vial with1,1,1,2-tetrafluoroethane.

The actuator employed in the case of all the formulations was a solutionactuator available under the trade designation “M3756” from 3M. Theelastomer employed in the valves in the case of all formulations wasthat available under the trade designation “DB-218” from American Gasketand Rubber Co. (Chicago, Ill.)

TABLE I Example Ingredient 1 2 3 4 5 6 7 Beclomethasone  0.1%  0.1% 0.25%  0.3%  0.4%  0.44%  0.5% 17, 21 Dipropionate Ethanol  3%    5%  10%    5%   10%   10%   15%   (anhydrous) 1,1,1,2- 96.9% 94.9% 89.75%94.7% 89.6% 89.56% 84.5% Tetra- fluoroethane

TABLE II Storage Time (Weeks) 0 2 4 7 12 % Recovery  101.4,  101.9, 100.8,  99.3, 100.6  98.7 101.6  99.6 95.5 102.6

The formulation of Example 1 did not exhibit precipitation of the activeingredient on freezing to −60° C.

The respirable fraction provided by the formulations of Examples 1-7 wasdetermined using an Anderson MK II Cascade Impactor with the averagerespirable fraction obtained from each being in excess of 40%. In thecase of the formulations of Examples 1 and 4, the respirable fractionwas about 76% and about 70%, respectively.

From the above data, it is believed that the optimum amount of activeingredient for low and high strength products would be about 0.08 and0.34 percent by weight, respectively, based on the total weight of theformulations.

EXAMPLE 8

A mixture containing 1.67 g of beclomethasone 17,21 dipropionate and 160g of cold (−65° C.) ethanol was homogenized using a Virtis 45homogenizer. The resulting suspension was placed in a one gallonstainless steel filling vessel equipped with a stir bar. A 1839 gportion of cold (−65° C.) 1,1,1,2-tetrafluoroethane was added to thefilling vessel. After about 5 minutes of stirring, a solution wasobtained. The resulting formulation contained 0.08 percent by weight ofbeclomethasone 17,21 dipropionate, 8.0 percent by weight of ethanol and91.92 percent by weight of 1,1,1,2-tetrafluoroethane. The formulationwas cold filled into aerosol vials and then 50 μL cold fill valves werecrimped onto the vials.

EXAMPLE 9

Using the general method of Example. 8, a formulation containing 0.34percent by weight of beclomethasone 17,21 dipropionate, 8.0 percent byweight of ethanol and 91.66 percent by weight of1,1,1,2-tetrafluoroethane was prepared. The formulation was cold filledas a suspension into aerosol vials which were then equipped with 50 μLcold fill valves. The formulation changed from a suspension to asolution as the vials warmed to room temperature.

EXAMPLE 10

A formulation containing 0.3 percent by weight of beclomethasone 17,21dipropionate, 10 percent by weight of ethanol and 89.7 percent by weightof 1,1,1,2,3,3,3-heptafluoropropane was prepared by i) weighing a 30 mgportion of beclomethasone 17,21 dipropionate into an aerosol vial ii)crimping a continuous valve onto the vial and iii) pressure filling witha solution containing 10 percent ethanol in1,1,1,2,3,3,3-heptafluoropropane.

What is claimed is:
 1. A method of preparing a solution aerosolformulation comprising the step of combining a therapeutically effectiveamount of beclomethasone 17, 21 dipropionate, a propellant selected fromthe group consisting of 1,1,1,2-tetrafluoroethane,1,1,1,2,3,3,3-heptafluoropropane, and a mixture thereof, and ethanol inan amount of 2 to 12 percent by weight to solubilize the beclomethasone17, 21 dipropionate in the propellant.
 2. The method of claim 1, whereinsaid formulation comprises 0.05 to 0.5% by weight beclomethasone 17, 21dipropionate.
 3. The method of claim 1, wherein said propellant ispresent in an amount of 88 to 98 percent by weight.
 4. The method ofclaim 1, wherein said formulation comprises 1,1,1,2-tetrafluoroethane asthe only propellant.
 5. The method of claim 1, wherein said formulationcomprises 1,1,1,2,3,3,3-heptafluoropropane as the only propellant. 6.The method of claim 1, wherein said formulation is free of surfactant.7. The method of claim 1, wherein said formulation consists essentiallyof a therapeutically effective amount of beclomethasone 17, 21dipropionate, a propellant selected from the group consisting of1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, and amixture thereof, and an amount of ethanol 2 to 12 percent by weight tosolubilize the beclomethasone 17, 21 dipropionate in the propellant.